The value of cytokeratin immunohistochemistry in the
evaluation of axillary sentinel lymph nodes in patients with
lobular breast carcinoma
G Cserni, S Bianchi, V Vezzosi, H Peterse, A Sapino, R Arisio, A Reiner-Concin, P Regitnig, J-P
Bellocq, C Marin, R Bori, J M Penuela, A Co ´rdoba Iturriagagoitia
............................................................... ............................................................... .
See end of article for
Dr Ga ´bor Cserni, Ba ´cs-
Kiskun County Teaching
Hospital, Nyiri u ´t 38, H-
6000 Kecskeme ´t,
Accepted for publication
10 October 2005
J Clin Pathol 2006;59:518–522. doi: 10.1136/jcp.2005.029991
Background: Cytokeratin immunohistochemistry (IHC) reveals a higher rate of occult lymph node
metastases among lobular carcinomas than among ductal breast cancers. IHC is widely used but is seldom
recommended for the evaluation of sentinel lymph nodes in breast cancer patients.
Objective: To assess the value of cytokeratin IHC for the detection of metastases in sentinel lymph nodes of
patients with invasive lobular carcinoma.
Methods: The value of IHC, the types of metastasis found by this method, and the involvement of non-
sentinel lymph nodes were analysed in a multi-institutional cohort of 449 patients with lobular breast
carcinoma, staged by sentinel lymph node biopsy and routine assessment of the sentinel lymph nodes by
IHC when multilevel haematoxylin and eosin staining revealed no metastasis.
Results: 189 patients (42%) had some type of sentinel node involvement, the frequency of this increasing
with increasing tumour size. IHC was needed for identification of 65 of these cases: 17 of 19 isolated
tumour cells, 40 of 64 micrometastases, and 8 of 106 larger metastases were detected by this means.
Non-sentinel-node involvement was noted in 66 of 161 cases undergoing axillary dissection. Although
isolated tumour cells were not associated with further lymph node involvement, sentinel node positivity
detected by IHC was associated with further nodal metastases in 12 of 50 cases (0.24), a proportion that is
higher than previously reported for breast cancer in general.
Conclusions: IHC is recommended for the evaluation of sentinel nodes from patients with lobular breast
carcinoma, as the micrometastases or larger metastases demonstrated by this method are often associated
with a further metastatic nodal load.
node have been known for decades,1 2but their prognostic
significance has been debated since their description.3Such
occult metastases can be demonstrated either by examining
deeper levels of the tissue blocks, or by using a more sensitive
method of detecting cancer cells. Immunohistochemistry
(IHC) has been used for this latter purpose, with the aim of
demonstrating epithelial markers. Retrospective studies,
generally with small case numbers, have proved inconclusive
for evaluating the prognostic significance of such occult
metastases,3which generally fall into the category of
micrometastasis or isolated tumour cells4 5(the latter also
referred to as submicrometastases6). Examination of step
sections is impractical when even moderate numbers of
lymph nodes have been removed, and would mean a huge
workload.7The same applies to the use of cytokeratin IHC. In
contrast, it is entirely feasible to use step sections and
cytokeratin IHC when sentinel lymph node biopsy is under-
taken, as these are the lymph nodes that are most likely to
harbour metastases.8If pathological efforts are concentrated
on these selectively recovered nodes, an improved staging can
be achieved.3 9Although recommendations vary on the use of
IHC for sentinel lymph nodes found to be uninvolved on HE
staining,6 10–16and most do not recommend its routine
use,6 10 13 14 16application of this technique is widespread both
in the USA and in Europe.6 17
Invasive lobular carcinoma (ILC) is known to produce
nodal metastasis that can be difficult to detect on HE stained
ccult lymph node metastases that are not detected by
the commonly used method of assessing a single
haematoxylin and eosin (HE) stained level per lymph
slides, as it is composed of non-cohesive cells of a similar size
to lymphocytes. Occult metastases of this tumour type
detected by IHC have been reported to be more common
Unfortunately the small number of cases of ILC investigated
in these papers does not give an indication of the effect of
occult metastases on recurrence and survival in this
histological tumour type.20Nevertheless, two later studies
with a longer follow up from the same institution suggested
that the presence of IHC-detected occult micrometastases in
either ILCs23or breast cancers in general24was not of
prognostic significance. However, these two follow up studies
did not distinguish between isolated tumour cells and
micrometastases as currently defined.4 16 25
Our present study was undertaken to assess the value of
cytokeratin IHC for the detection of metastases in sentinel
lymph nodes from patients with ILC.
A previous study by the European Working Group for Breast
Screening Pathology (EWGBSP) evaluated current practice
concerning sentinel lymph nodes in European pathology
laboratories.17EWGBSP members working in laboratories
where cytokeratin IHC is used routinely for sentinel nodes
found negative on multilevel HE assessment were asked to
collect data on cases diagnosed as ILC and staged on sentinel
Abbreviations: EWGBSP, European Working Group for Breast
Screening Pathology; IHC, immunohistochemistry; ILC, invasive lobular
node biopsy. The details reported included the metastatic
status of the sentinel lymph nodes, the method of detection
of sentinel node involvement (HE versus IHC), and further
nodal involvement. Patients were not identified during this
retrospective data collection and analysis, and therefore no
ethics approval was necessary.
For the purpose of this study, any tumour cell in a sentinel
lymph node was considered a positive finding. Nodal
involvement was then categorised as isolated tumour cells,
micrometastases, or macrometastases according to the
definitions of these categories within the EWGBSP guide-
lines.4 5 26
The laboratories contributing cases to the current study
had different histological protocols relating to the work-up of
the sentinel lymph nodes, but all departments embedded the
whole node if it was considered negative on macroscopy.
Nodes greater than 5 mm diameter were sliced into pieces
and all departments used the approach of multilevel HE
staining and routine cytokeratin immunostains if the HE
slides were negative. Further details are given in table 1.
Data on sentinel lymph node biopsies from 449 ILCs were
collected and analysed. Altogether 189 patients (42%) had
sentinel node involvement of any type. This rate varied from
institution to institution (range 29% to 55% (SD 9%); table 1).
The rate of nodal involvement increased with increasing
tumour size as expected (table 2). A similar relation with
tumour size was seen with HE detected nodal involvement
and macrometastases, but not with IHC detected nodal
involvement, isolated tumour cells, or micrometastases
HE staining detected most of the metastases. Although
most of these metastases were classified as macrometastases,
some micrometastases (24 of 64; 0.38) were also identified by
this method, and a few isolated tumour cells were also picked
up on HE stained slides (table 4). IHC alone identified 34% of
all cases of nodal involvement. This rate also varied from
institution to institution (range 22% to 50% (SD 10%), the
latter being an outlier with small amounts of data (table 1)).
Although the category of nodal involvement where IHC
resulted in the greatest increase in the rate of detection was
isolated tumour cells (17/19; 0.89), a significant proportion of
the micrometastases (40/64; 0.63) were also detected by IHC,
and some larger metastases were also demonstrated by this
means (8/106; 0.08). The median size of the macrometastases
was 2.75 mm (range 2.1 to 7.0 mm), and all could be verified
on HE in retrospect, after the IHC results were available
(figs 1 and 2).
Data on non-sentinel lymph nodes were analysed only in
cases with sentinel node involvement. The database included
one case of a false negative sentinel node biopsy, where
axillary dissection revealed a single metastatic non-sentinel
node out of 11 nodes recovered, and this was associated with
a negative examination of the sentinel node. Axillary
dissection was carried out in 44 patients without sentinel
node involvement as part of the validation phase of sentinel
node biopsy. By contrast, axillary clearance was omitted in 28
cases with an involved sentinel node (tables 3 and 4). This
was either because of sentinel node involvement by isolated
tumour cells or micrometastases only, or because of the
participation of several patients in the European Organisation
for Research and Treatment of Cancer (EORTC) trial, ‘‘After
(AMAROS), randomising patients with positive sentinel
lymph nodes between axillary dissection or radiation therapy.
In all, 161 cases with involved sentinel lymph nodes
underwent axillary dissection. Isolated tumour cells and
Methods used for the evaluation of grossly negative sentinel lymph nodes and basic characteristics of contributed
by principal investigator
No of HE levels assessed per SLN
(distance between levels)No of IHC levels (antibody)
No of cases entered in this
analysis (IHC positive/all
BianchiMultilevel until extinction of the
blocks* (0.1 mm)
>6 (distance not specified)
4 (0.01 mm)
Multilevel until extinction of the
Multilevel until extinction of the
blocks* (0.25 mm)
Multilevel until extinction of the
blocks* (0.125 mm)
Multilevel until extinction of the
blocks* (0.5 mm)
Multilevel until extinction of the
blocks* (0.25 mm)
10 (0.04 mm)
Multiple (AE1/AE3) 146 (25/62)17 (7)
1 (CAM 5.2)
Multiple (KL1; EMA)
Multiple (mean 8) (AE1/AE3)
Reiner-ConcinMultiple (AE1/AE3)33 (5/12)21 (15)
RegitnigMultiple (MNF-116)33 (5/12)21 (15)
BellocqMultiple (KL1)32 (4/17)27 (18)
CserniMultiple (PanCK or MNF-116 or
29 (4/11)19 (11)
Martinez Penuela7 (1/2)13 (4)
*For lymph nodes negative on macroscopy and/or intraoperative assessment only.
HE, haematoxylin and eosin; IHC, immunohistochemistry; SLN, sentinel lymph node.
Rate of nodal involvement according to tumour size
Proportion of SLN
0.1 to 1.0
1.1 to 2.0
2.1 to 3.0
3.1 to 4.0
SLN, sentinel lymph node.
Cytokeratin detected metastases in lobular cancer519
micrometastases in the sentinel lymph nodes were associated
with a low rate of non-sentinel node involvement (0 and
0.14, respectively; 0.11 overall), whereas, as expected, the
rate of macrometastases associated with non-sentinel node
metastases was higher (0.60). Sentinel lymph node involve-
ment first detected by IHC was associated with a considerable
rate of non-sentinel node involvement (0.24), as some of the
involvement detected by IHC was due to macrometastases,
five of eight of these cases being associated with non-sentinel
node metastases (table 5).
Cytokeratin IHC of unselected axillary lymph nodes from
patients with ILC has been shown to upstage these patients
more often than those with ductal carcinoma,20 23and some
laboratories have therefore introduced this method as a
routine means of evaluating all lymph nodes removed in this
subset of patients.27As sentinel lymph node biopsy selects the
nodes which are the most likely sites of regional metastases,
it would be wiser to limit the use of IHC to these nodes. Most
guidelines do not recommend IHC for the evaluation of
sentinel lymph nodes in general practice,6 10 13 14 16but it may
be used in special cases, such as cases of ILC.6As sentinel
node biopsy is as reliable in ILC as in ductal cancers,28 29we
evaluated the role of cytokeratin IHC in a multi-institutional
cohort of ILC patients who underwent sentinel lymph node
Our results show that tumour size influences the nodal
involvement in lobular carcinoma. This finding is consistent
with nodal involvement being more common in larger
tumours of any histological type. Although no comparison
was made between the rate of nodal involvement in different
types of tumour, our results are in agreement with data from
the era before sentinel node biopsy. We found that 34% of all
cases of nodal involvement were detected by IHC, which is
higher than the rate reported for breast carcinoma in general
or of ductal carcinoma, and is in the rate range reported for
ILC.18–22 29Although there were institutional methodological
variations in this retrospective study, and also differences in
the rate of nodal involvement and IHC positive cases, these
latter differences can only partly be accounted for by the
methodology. Mean tumour sizes were also different
(table 1), and this may have altered the metastatic rates
mentioned above. Obviously, the more detailed the histolo-
gical protocol, the more positive cases will be detected.30 31
Diversity of methods may be a problem with this study, but
such variations in methodology can be found when compar-
ing the various studies cited previously,18–22and are encoun-
tered in nearly all reviews dealing with the upstaging role of
IHC in breast cancer.32Owing to the large number of cases, it
is felt that the conclusions below can be relied upon, even if
there may be some variation in the pathological approach to
the reported lymph nodes.
To the best of our knowledge, this is the first report on the
differential rates of isolated tumour cells, micrometastases,
and larger metastases detected by IHC. Surprisingly, despite
the fact that the isolated tumour cell category of nodal
involvement was the one in which IHC produced the greatest
increase in detection rate (17/19; 0.89), the largest category of
IHC-detected nodal involvement (n=40) was the micro-
metastases. This is probably because ILC often produces
involvement of the nodal parenchyma,33and we considered
this to represent micrometastasis.25 26Obviously, a smaller
number of macrometastases was also first detected by IHC.
The displacement and passive transport of tumour cells
after needling procedures and excision biopsy34–36have been
proposed as a mechanism for the lodging of tumour cells in
regional lymph nodes, especially in sentinel lymph nodes
from breast cancer patients. The phenomenon of artefactual
tumour cell seeding has been seen in cases of ductal
carcinoma in situ37and, although this event may be rarer in
the less cellular but less cohesive lobular carcinomas, isolated
intrasinusoidal epithelial cells may well be of this origin. It
has been postulated that these cells are detectable mainly by
IHC only, and therefore that the IHC detected cells are
Differential rate of nodal involvement according to tumour size
size (cm) ITCsMicrometastasesMacrometastases IHCHE All
0 to 1.0
1.1 to 2.0
2.1 to 3.0
3.1 to 4.0
HE, haematoxylin and eosin; IHC, immunohistochemistry; ITC, isolated tumour cells.
dimension (Cytokeratin AE1/AE3; original magnification 6400).
IHC detected metastasis measuring 2.5 mm in its greatest
Tumour cells could be verified with this stain, but were not as obvious
(original magnification 6400).
HE stained slide from the same case as shown in fig 1.
520Cserni, Bianchi, Vezzosi, et al
irrelevant. Patients undergoing prophylactic mastectomies
after biopsies were only rarely found to have IHC detected
epithelial cells in their sentinel nodes, however.38This
suggests that cancer needs to be present for there to be an
increased rate of IHC positive sentinel nodes after biopsy or
other means of physical manipulation of the tumour. These
diagnostic or therapeutic procedures alone cannot be
responsible for all cases of IHC detected nodal involvement.
A word of caution is required, as cytokeratin positive nodal
structures cannot always be equated with metastatic nodal
involvement. Besides the artefactually displaced tumour cells
discussed above, normal constituents of the lymph nodes
may also stain with anti-cytokeratin antibodies. Interstitial
reticulum cells have been reported to be cytokeratin positive,
especially when stained by CAM5.2 or an in-house cytoker-
atin cocktail, whereas this was much rarer or absent with
AE1/AE3.39 40Plasma cells have also been reported to stain
with CAM5.2 and pan-cytokeratin.40Rarely, occasional cells
compatible with histiocyte morphology also stain weakly
with cytokeratin antibodies. Obviously, rare epithelial inclu-
sions of the lymph nodes are also cytokeratin positive.41
Morphology should therefore never be neglected in the face
of positive cytokeratin staining, and this will usually help to
discriminate cancer cells from the others. Whenever there is
doubt as to the nature of cytokeratin positive cells, these
should not be called metastases, in line with the general rules
of the TNM staging of cancers.42None of the cytokeratin
positive cells in this study was considered to represent
inclusions or non-epithelial cells.
Although the rate of nodal involvement increased with
increasing tumour size, and this was also true for the
macrometastases; the rate of nodal involvement, isolated
tumour cells, and micrometastases detected by IHC tended to
decrease with increasing tumour size (tables 2 and 3). The
lack of an association between IHC detected sentinel node
involvement and predictors of HE detected sentinel node
involvement was reported earlier.37Although this may be
because isolated tumour cells are commonly (although
certainly not always) the result not of a true metastatic
process but rather of previous procedures and manipula-
tions,37another possible explanation could be that IHC tends
to detect less obvious nodal involvement (generally falling
into the category of isolated tumour cells or micrometas-
tases), which is more common with smaller tumours,
whereas larger tumours have already established larger
metastases that are more likely to be detected by HE staining
even in ILC.
Although we were unable to analyse the prognostic
significance of these metastases in terms of relapse or
survival, we did analyse the status of further lymph nodes
in the axilla in the 161 patients who had an axillary
dissection after the diagnosis of sentinel node involvement
of any type. Twelve of 50 IHC detected sentinel lymph node
metastases from ILC, but none belonging in the isolated
tumour cell category, were associated with non-sentinel node
involvement, which was higher than our previous meta-
analysis (around 9%) would have suggested for IHC detected
sentinel node involvement in breast cancers in general.32
None of the studies included in that meta-analysis drew
conclusions in relation to the histological type of tumour.
Our findings suggest that sentinel lymph nodes should be
investigated by IHC if the primary tumour is of lobular type,
because this approach may often detect micrometastases and
even larger metastases, requiring further axillary treatment
by current standards.
GC is supported by a Ja ´nos Bolyai Research Fellowship from the
Hungarian Academy of Sciences. AS is supported in part by the
Ministero dell’Universita e della Ricerca Scientifica es Tecnologica
G Cserni, R Bori, Department of Pathology, Ba ´cs-Kiskun County
Teaching Hospital, Kecskeme ´t, Hungary
S Bianchi, V Vezzosi, Department of Human Pathology and Oncology,
University of Florence, Italy
H Peterse, Department of Pathology, The Netherlands Cancer Institute,
A Sapino, Department of Biological Science and Human Oncology,
University of Turin, Turin, Italy
R Arisio, Department of Pathology, Sant’Anna Hospital, Turin, Italy
A Reiner-Concin, Institute of Pathology, Donauspital, Vienna, Austria
P Regitnig, Institute of Pathology, Medical University Graz, Graz,
J-P Bellocq, C Marin, Department of Pathology, Ho ˆpital de Hautepierre,
J M Penuela, A C Iturriagagoitia, Department of Pathology, Hospital de
Navarra, Pamplona, Spain
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HE, haematoxylin and eosin; IHC, immunohistochemistry;
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as the micrometastases or larger metastases demonstrated by
this method are often associated with a further metastatic
Cytokeratin detected metastases in lobular cancer521
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522Cserni, Bianchi, Vezzosi, et al